There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. These individual differences in behavioral responses to drugs also display substantial genetic and environmental influences, are continuously distributed, and appear to be influenced by many genes rather than one or two major genes. For these reasons, application of several of the techniques of genetics and molecular biology could be helpful in identification of genetic influences in readily-studied experimental animals that could shed light on human interindividual differences, and identify genes potentially responsible for behavioral variation in drug responses in these animals. Recombinant inbred strains have been tested for cocaine-induced locomotor responses, sensitization and F2 mice to identify gene loci associated with these phenotypes. Animals from a heterogenous stock have been tested for cocaine-induced locomotor activation, and have been used to establish a genetic selection paradigm to ask if selection for cocaine-induced locomotion also selects for other cocaine-induced functions, including psychomotor stimulant conditioned place preference measures. Each of these approaches will allow improved assessment of genetic influences in substance abuse, and analyses of the recombinant inbred strain comparisons will allow chromosomal mapping of specific genes contributing to the strain differences through quantitative trait locus approaches.